Leukotriene A.sub.4 (hereinafter referred to as LTA.sub.4) hydrolase, which is one of epoxide hydrolases, is a metal-containing enzyme which requires zinc in its active center.
LTA.sub.4 hydrolase plays a catalyst-like role on biochemical conversion from LTA.sub.4 into leukotriene B.sub.4 (hereinafter referred to as LTB.sub.4), which is a strong pro-inflammatory substance.
LTB.sub.4 is an arachidonic acid metabolite which is produced in 5-lipoxygenase pathway, is biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage, etc., and plays a role as an important mediator in inflammation. LTB.sub.4 induces chemotaxis, aggregation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood-vessel permeability and edema formation. For this reason, it was reported that a particularly high level of LTB.sub.4 is detected at lesion sites in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66 1166-1170 (1980)), psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory bowel diseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2, 1122-1124 (1982)), and in sputum in cystic fibrosis (Lancet, 342, 465-469 (1993)).
Accordingly, compounds which inhibit LTA.sub.4 hydrolase are expected to prevent production of LTB.sub.4 and exhibit therapeutic effects on inflammatory diseases.
It was reported that 3-oxiranylbenzoic acid and derivatives thereof have inhibitory effects on LTA.sub.4 hydrolase and are useful as therapeutic agents for inflammatory diseases such as psoriasis, inflammatory bowel diseases, arthritis and gout (Japanese Laid-open Patent Publication No. 134375/1990).
It was also reported that (+)-1-(3S, 4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentanecarboxylic acid had an inhibitory effect on LTA.sub.4 hydrolase and inhibited the onset of arthritis in a collagen-induced arthritis model (J. Med. Chem., 37, 3197-3199 (1994)).
On the other hand, structural features of the present compounds represented by the general formula [I] are that a sulfur atom of sulfur-containing amino acids such as cysteine is bonded to a substituted phenylalkyl group and an N-terminal is bonded to a sulfur-containing branched lower alkanoyl group. Prior art publications are described hereinafter from the standpoint of chemical structure. ##STR2##
The following two kinds of known compounds have similar chemical structures to those of the present compounds; compounds of which R.sup.3 is a hydrogen atom and compounds of which R.sup.4 is a benzyl group in the general formula [I]. It was reported that diastereomers of the former compounds have inhibitory effects on ACE (Chem. Pharm. Bull., 35, 2382-2387 (1987)) and optically active substances of the former compounds have inhibitory effects on ACE and inhibitory effects on endopeptidase 24.11 (J. Med. Chem., 37, 2461-2476 (1994)). It was reported that the latter compounds are useful as therapeutic agents for rheumatoid diseases and antihypertensives since they have inhibitory effects on ACE and inactivating effects on rheumatoid factors (Japanese Laid-open Patent Publication No. 165362/1986), they have inhibitory effects on endopeptidase 24.11 and are useful for treatment of hypertension (Japanese Laid-open Patent Publication No. 39855/1988), and they enhance natriuretic effects of endogenous ANF and are useful for treatment of hypertension and congestive heart failure (Japanese Laid-open Patent Publication No. 503799/1990).
However, no inhibitory effect on LTA.sub.4 hydrolase is described in the reports.
As mentioned above, various studies were carried out, focusing attention on the inhibitory effects on ACE, the inhibitory effects on endopeptidase 24.11, the inactivating effects on rheumatoid factors and the enhancement of natriuretic effects of endogenous ANF of the sulfur-containing amino acid derivatives. However, no study was carried out at all, focusing attention on the inhibitory effects on LTA.sub.4 hydrolase about the sulfur-containing amino acid derivatives. It is a very interesting subject to study which compound has the inhibitory effect on LTA.sub.4 hydrolase and how the introduction of various substituents into the compound influences the above-mentioned effect.